Peripheral neuropathy significantly complicates and prolongs recovery in 20% or more of extensively burned patients. The etiology and pathogenesis aare poorly understood. We are investigating the effects of thermal injury on peripheral nerve function using in vivo injury models and a variety of functional and biochemical studies. The role of altered regional blood flow (NBF) and its interrelationships with endoneurial and wound edema comprise an important additional focus. There is a differential vulnerability to heat of sensory vs. motor A alpha axons in vivo and in vitro; this conduction block is reversible in vitro by 4-aminopyridine and other potassium channel blockers. The characteristics and mechanisms of this phenomenon will be explored: 1) by determining whether in vivo heat block is also reversible and if so, to address the effector mechanisms, not only of conduction block, but also of restoration of nerve function, which clearly has clinical relevance; 2) the use of single fiber studies, supplemented as necessary by electron microscopy and by biochemical characterization of changes in myelin protein kinetics and protein-lipid complexes, as they may correlate with conduction block and its pharmacological reversal, will aid in explaining these phenomena. Neurotoxic materials appear to be formed in the burn wound; they will be characterized chemically; more severe injury models will be used to determine whether remote nerves also demonstrate functional abnormalities and/or whether wound extracts induce abnormalities in normal nerves. Using 14C butanol distribution, which permits simultaneous quantitation of blood flow in nerve, muscle and skin, and the servo-null micropipette technique for measurement endoneurial tissue pressure, we will systematically assess the role in conduction failure of altered nerve blood flow and its interrelationships with endoneurial and wound edema following both injury and fluid resuscitation. Concomitantly, present methodology will be adapted to permit simultaneous quantitation of spinal cord blood flow (SCBF). Physiological studies addressing the regulation and magnitude of NBF and SCBF will be extended, as such data is presently largely lacking and is necessary for the interpretation of data from injured subjects. Conditions pertinent to trauma such as hypotension, anesthesia, fluid resuscitation, vasoactive drug administration, etc. will be investigated. The project brings together one investigator with expertise in the pathophysiology of injury and another with long experience in peripheral nerve physiology. Functional consultative associations have been developed with neurobiologists with relevant expertise.